Covering the whole development process for the global biotechnology industry

Bioprocessing begins upstream, most often with culturing of animal or microbial cells in a range of vessel types (such as bags or stirred tanks) using different controlled feeding, aerating, and process strategies.

Beginning with harvest of material from a bioreactor, downstream processing removes or reduces contaminants to acceptable levels through several steps that typically include centrifugation, filtration, and/or chromatographic technologies.

Drug products combine active pharmaceutical ingredients with excipients in a final formulation for delivery to patients in liquid or lyophilized (freeze-dried) packaged forms — with the latter requiring reconstitution in the clinical setting.

Many technologies are used to characterize biological products, manufacturing processes, and raw materials. The number of options and applications is growing every day — with quality by design (QbD) giving impetus to this expansion.

Even as it matures, the biopharmaceutical industry is still a highly entrepreneurial one. Partnerships of many kinds — from outsourcing to licensing agreements to consultancies — help companies navigate this increasingly global business environment.

No matter what the industry, it’s widely accepted that slow-moving companies give their nimbler competitors an advantage, allowing them room to dominate the market even if their products are not superior. “Me-too” products and their sponsors often are seen as followers rather than leaders — even if they offer improvements over what is already available. Fast movers are flexible and adaptive to a dynamic business environment. They capitalize on opportunities and navigate risks and challenges by responding quickly to changes — or better yet, anticipating them. In some industries, speed can be achieved through supply chain compression, project management streamlining, automation, outsourcing, inventory control, and Internet/cloud-based collaborations. Some businesses even have the option of putting out “minimum viable products” just to get there first and then improving them for subsequent releases. Although some of those tactics may work in drug development to varying degrees, the latter tactic most definitely will not.

“Speed to market” is a 21st-century catch phrase for many disparate industries, from insurance to e-commerce and beyond. What often brings it home for many biopharmaceutical companies is replacing the word market with the word clinic. The highly regulated healthcare market will not tolerate release of products that compromise on quality, safety, or efficacy. In fact, most drug candidates that go into development will never make it out successfully. And yes, some drug sponsor decision-makers might see regulations as hampering their ability to operate — until, perhaps, they find themselves in need of some vital medicine for their own personal health, when surely they will expect that product to be as trustworthy as it possibly can be.

At the 2018 BioProcess International Conference and Exhibition in Boston last fall, “Speed from Gene to Market” was both a conference track of its own and an underlying theme of the entire program, with talks on process intensification, data management, and compressing timelines drawing much interest throughout the week. After the meeting, I talked with BPI editorial advisor Susan Dana Jones (principal consultant at BioProcess Technology Consultants) and Sourav Kundu (senior director of biologics R&D at Teva Pharmaceuticals) about some general approaches to truncating the timespan from candidate nomination to filing an investigational new drug (IND) application.

“The approaches to shortening timelines and enabling rapid entry into clinical development include risk assessment, limiting development activities, using process and analytical platform approaches, and efficiently integrating all aspects of production of drug substance and drug product,” Jones said. “An efficiently managed program with no major setbacks in development can progress from gene to IND filing in about 18–20 months if it is outsourced, and somewhat less time if all activities are controlled and performed by a single entity.”

“Most companies now have a platform for MAbs to bring a molecule to the clinic for the first time (first-in-human process),” Kundu said, “which substantially cuts down time and resources. Even for commercial process development, it is now mostly platform. The facilities can be built very quickly with modular approaches using single-use equipment (at lower cost), which substantially reduces the risk, investment, and time to market.” But, he cautioned, non-MAb therapeutics and cell therapies face “a whole different set of challenges.”

Once a product is in clinical development, accelerating its progress to market means conducting chemistry, manufacturing, and controls (CMC) activities to make a product ready for phase 3 as soon as is feasible. “Many companies are using prior knowledge to reduce process characterization work and shortening the timeframe and investment there,” Kundu explained. “There are additional aspects of getting everything ready for launch when planning and experience can shorten the timeframe. You are still going to be driven by the speed of the clinical trial, but the point is to have everything else ready while the trial is ongoing. Obviously, this brings additional risks to the program as you are investing money without knowing that the clinical trial will be successful but that is up to the company to decide.”

“You probably didn’t take the time to make a working cell bank (WCB) before IND filing,” Jones said, “but now is the time to invest in a WCB that will be used for your late-stage process. At least a few batches should be run to generate a range of process information even if the product will not be needed immediately for the clinic.” To get to a final process as soon as possible, companies should begin risk assessment, identification of critical process parameters (CPPs), and process optimization well before then.

“Postapproval changes are possible,” she pointed out, “so if the goal is ‘fast to market,’ then do what you can in the time available.” That’s the drug industry’s take on the “minimum viable product” idea — but it’s more about a “minimum viable process,” which means one that yields a drug of the necessary quality if not in the most efficient way. Changes can be made later to improve on cost or speed, for example, so long as they can be demonstrated not to affect quality. Any resulting alteration of product characteristics must be documented not to affect safety, quality, or efficacy.

Such testing and documentation costs money. Thus, many experts recommend putting as much effort as possible into early process development and optimization. “Companies should focus on what is important for their product,” Jones said. “If the dose will not be high, then consider limiting investment in upstream development to activities that ensure robust, reproducible production rather than expression-level increases. Determine the operating ranges for your process with limited design of experiments (DoE), and don’t invest much time in expanding the design space. This approach will lead to a few more batch failures, but it will save time, and the risk/benefit for each product should be carefully considered.”

Platforms and Novel Technologies
I asked Jones about bottlenecks in bioprocess development. For one thing, I’d heard a lot of talk about shortening cell-line development timelines last year. “Cell-line development is not going to get much shorter than it already is,” she cautioned, “because it takes time to identify a cell line, confirm the genetic stability, and do the cell banking and testing.” After performing at least one round of cloning, most companies use imaging, fluorescence-activated cell sorting (FACS), or other strategies to demonstrate and confirm single-cell origin of their master cell banks (MCBs) (1). “The minimum time to do so is about eight weeks, but that is followed by another 14 weeks of genetic stability testing. So the way to shorten the timeline is to invest money in multiple MCBs as soon as two to five candidate clonal cell lines have been identified — and to use all those cell lines in process development.” Another time-saving strategy may be to pool candidate clones to produce materials for toxicology testing, she said, but the few companies that have done so find that it requires extensive and sophisticated analytical capability to confirm that subsequent clinical batches are comparable to those early drug substances.

“There are many new technologies for clone development and screening that are very promising and actually being used already,” Kundu said. “One example is Beacon technology (from Berkeley Lights), which can screen clones very fast and with much accuracy. Technology now can isolate high-producing clones very accurately and also can expand the number that can be screened, increasing the probability of success.”

Shifting focus to biomanufacturing, I wondered whether identified bottlenecks in certain upstream and downstream operations represent particularly good places to make changes and speed development along. Kundu first pointed out the value of modular facilities and single-use technologies to reduce the time it takes to build and validate facilities.

“Upstream, there have been some advances in selecting parental and clonal cell lines that have shorter doubling times,” Jones said, but she believes there will never be Chinese hamster ovary (CHO) cells that can double in under ~18 hours. “Downstream has some options for improving the overall time to produce a batch of product, including continuous processing, increased use of membrane chromatography, and improved clarification strategies.” Those can reduce the complexity of material loaded on to the first chromatography step often referred to as “capture” — for example, the protein A affinity column in a monoclonal antibody (MAb) process. “Overall, the actual process is not going to get a lot faster. More investment in quality control (QC) could accelerate product release after production. Good integration with hand-off from drug substance to drug-product manufacturing will have a much great impact on overall timelines for release of product to the clinic or the market.”

Three BPI presentations addressed biomanufacturing aspects of timeline compression in the Speed from Gene to Market track: “Seamless Integration of Projects Between R&D and Manufacturing,” by Gene Lee (senior director of protein and cell sciences in discovery and development technologies at the EMD Serono Research and Development Institute); “Accelerating Biologics Process Development: Leveraging Platform and Novel Technologies,” by Hang Yuan (senior director of biologics process development at Shire); and “Overcoming Challenges for Developing a Robust Downstream Process for Early Phase ADC Manufacturing Under Tight Timelines,” by Chi Zhang (process development scientist at Ambrx Inc.).

A Benchmarking Study: In a concurrent BPI eBook presentation, Lee and coauthors from EMD Serono and the Latham Biopharm Group (LBG) expanded on the discussion of their collaborative project (2). Through an industry benchmarking survey spearheaded by LBG, the biomanufacturer identified areas where it was lagging behind industry best practices and determined ways to improve. For example, project timelines from gene transfection to pilot toxicology testing were about 33% longer than those of the benchmark companies. By using platform technologies, optimizing processes, and making productivity improvements where possible, the company has streamlined development timelines for critical-path activities. For example, whereas it once took 11 months to go from clone selection to release of toxicology material, now the same timeline is down to three months. EMD Serono’s focus is now trifold: to shorten timelines to first-in-human studies by streamlining development and removing multiple points of technology transfer, to increase efficiency in CMC development, and to establish strong crossfunctional engagement for true collaboration throughout the organization.

Intensification Technologies: Yuan focused on Shire’s upstream process intensification through transitioning from fed-batch to perfusion cell culture using a Sartorius Stedim Biotech ambr system. He too highlighted cross-functional integration and collaboration as essential to success. Platform approaches are very effective, he said, to speed up development both for MAb and non-MAb molecules. New technologies can be applied to relieve process bottlenecks. In this case, the centrifuge-based perfusion process provided 3–5× productivity over the fed-batch process using the same medium. He also showed how automated high-throughput analytical and purification with online product-quality testing round out this modern approach.

With a challenging antibody–drug conjugate (ADC) product in the works, Ambrx faced complexities in downstream process development. With three different contract manufacturing organizations (CMOs) playing key project roles around the world, coordination among them was pivotal to success. The timeline was tight: only six months allotted for completion of process development and technology transfer to the CMO. That allowed for just a single toxicology run and one good manufacturing practice (GMP) manufacturing run, with no backups. But significant quantities of drug substance were needed for toxicology studies within two months. And there was no platform process to start with.

To address those challenges, Ambrx developed its upstream and downstream processes in parallel. They were designed to fit into the CMO facilities with only minimal changes, using CMO-approved materials wherever possible. The work was based on key performance indicators (KPIs) and critical quality attributes (CQAs) from a previously developed ADC that already was in clinical trials. One unique solution was to use feedstocks from the toxicology run for viral clearance testing, which removed a possible bottleneck from the timeline to IND submission. And finally, incremental scale-up by the CMOs and focused, in-house robustness studies were used to verify that the developed process was good enough for GMP manufacturing.

Zhang said that the parallel development approach saved overall time, with the robustness study aiding in risk mitigation. Early identification of KPIs and CQAs increased efficiency in process development. Detailed technology-transfer documents prevented trouble, and the results of this work can help Ambrx develop a platform process for ADC manufacture.

Failure is an Option
Biopharmaceutical companies have to strike a balance between the optimism of working ahead and the realism of accepting failure as an option. Depending on who’s making the estimate using which criteria, at least half of all drug candidates identified during lead optimization will not make it through the clinical phases to market. Such failures manifest as a process of attrition in the overall drug pipeline and create cost pressures because the products that do succeed must earn enough money to make up for those that do not. In a stage-gate product development framework, systematic, crossfunctional reviews increase the scrutiny on R&D programs over time, with key decisions made at each important project milestone (“gates”) to assess “what has been achieved, whether it is sufficient, and based on the information available whether the project can be sanctioned to the next stage” (3). This allows corporate management to pause or abandon a project completely as a means of preventing resources and effort from being wasted on doomed products.

Developability: At the 2018 BPI Conference, Daniel Heitmann (head of portfolio and project management at Novartis Pharma) discussed such developability assessments in “Enhancing Speed in Development By Early Quality Assessment of Biologics.” He showed how Novartis screens for such criteria as stability, solubility, and immunogenicity based on expression/production, purification, and analytical method “toolboxes.” Using such platforms, the company can accelerate development of upstream and downstream processes as well as analytical methods. Platform cell lines are suitable both for making clinical supplies and for final commercial processes. Only
the best candidate drug-substance molecules (technically speaking) will progress into clinical development. And early assessment of a drug-product “formulation space” helps make an early dosage form available for clinical studies. Heitmann showed how early risk assessment is part of developability screening. He said the approach “enables strategic portfolio decisions for aggressive accelerations or low-resource developments” and helps the company make “accurate estimates for process scales and supply forecasts.”

Cell-Line Development: Failure also is an option — even the norm — for production cell lines in development. Every biomanufacturing process begins with transfection of recombinant genes into pools of cells — and a succession of screenings that follow will weed out far more cells than they allow to pass through. The losers will be those that do not uptake the correct genetic material, those incapable of thriving in bioprocess conditions, those that fail to produce recombinant protein at relevant levels, and those without demonstrated clonality and relative genetic stability. And as with drug-substance candidates, it’s better for those failures to occur early than after time and resources have been wasted on the losers.

At the 2018 BPI Conference, that was clear in two presentations: “Speeding Up Cell Line Development: Implementing Novel Technologies to Reduce Timelines,” by Thomas Jostock (science and technology lead in integrated biologics profiling at Novartis Pharma); and “Experiences and Challenges During the Commercialization of a Monoclonal Antibody,” by Jeffrey Ly (associate principal scientist in biologics process development and commercialization at Merck).

Jostock said that his team is “pushing the timelines of cell line devlopment close to the biological limit.” At Novartis, as Heitmann too had shown, a mammalian and microbial cell-line development and developability assessment are the work of a common organization unit called “Integrated Biologics Profiling.” That group has applied technology advancements to speed up cell-line engineering (vectors and expression systems) and screening/ranking. Using “fast-track cloning,” a project can go from DNA transfection to high-producing clones in just eight weeks based on an aggressively accelerated pool generation, a FACS vector technology for single-cell cloning and preselection, and final clone screening in an ambr system.

Ly showed how Merck updated its own procedures to meet current regulatory expectations regarding clonality based on genotypic, product quality, and phenotypic results from analyzing 24 subclones. With conserved banding patterns (genotypic analysis) and comparable product-quality results across all subclones, and phenotypic observations consistent with those of a clonally derived cell line, the team can provide assurance that consistent and specified-quality drug substance can be manufactured.

Another challenge Merck faced was variation in product quality from one bioreactor batch harvest to the next. “Combined variable feeding strategies based on metabolite concentrations,” Ly explained, “can lead to process robustness issues if variability in cell culture performance is present.” So process engineers modified the procedures to improve bioreactor titer robustness using the same raw materials as the original process and yielding comparable product quality. High-throughput, multivariate data analysis helped identify correlating factors.

Regulatory Strategies
No matter how fast a drug maker can move, its product remains at the mercy of regulatory oversight and review. I asked Jones how she sees regulators responding to this increasing focus on speed. “The FDA has adopted a risk-based approach to assessment of manufacturing strategies,” she told me, “that enables more limited development ahead of phase 1 studies as long as product quality and patient safety are maintained. So speed to clinic can be accelerated with commitments to gain further process understanding and product-quality evaluation later in development.” She pointed out, however, that such risk-based assessment has not been widely adopted outside the United States.

When it comes to product development (rather than process development), different regulators do offer some ways to assist companies working on particular sorts of drugs. The EMA and FDA boxes summarize options available in Europe and the United States. “Fast-track and breakthrough designations do not reduce the agency expectations for a full CMC development program,” Jones cautioned, “so no short-cuts that could impact process robustness can be applied to commercial process development for these products.”

The EMA Priority Medicines Program

In 2016, the European Medicines Agency (EMA) launched its Priority Medicines (PriMe) scheme to enhance support for medicines targeting unmet medical needs. Enhanced interactions and early dialogue between developers and the agency help optimize generation of robust data on risks and benefits to enable accelerated application assessment. The goal is to get the resulting medicines to patients as quickly as possible.

Accelerated Assessment: PriMe builds on an existing regulatory framework and available scientific advice and accelerated assessment options. Early engagement is meant to improve clinical trial designs for better results, helping companies make the best use of limited resources.

Key Benefits for Applicants: Once a PriMe candidate medicine is selected, the EMA will assign a dedicated contact and

appoint a rapporteur from the Committee for Medicinal Products for Human Use (CHMP) or the Committee on Advanced Therapies (CAT) to provide continuous support

organize a kick-off meeting with a multidisciplinary group of experts to provide guidance on overall strategy

Eligibility Criteria: The PriMe scheme prioritizes medicines that offer a major therapeutic advantage over existing treatments or that will benefit patients with no other treatment options. Early clinical data must show a candidate’s potential to benefit patients with unmet medical needs.

“I think the regulators are in favor of speed to market for critical illnesses,” Kundu pointed out, “particularly in the oncology area, where there are very few options. In some cases, companies that have received fast-track designation are struggling to get everything else done to take advantage of the process.”

FDA Acceleration Programs

Making treatments for serious diseases available as quickly as possible is in everyone’s interest. The US Food and Drug Administration (FDA) has developed four distinct approaches to doing so: accelerated approval, breakthrough therapy, fast track, and priority review.

Accelerated Approval: It takes many years to determine whether a drug candidate actually provides a clinically meaningful benefit to patients’ survival or quality of life. In 1992, FDA instituted accelerated-approval regulations to base on surrogate endpoints approvals of drugs filling unmet medical needs for serious conditions. Section 901 of the 2012 Food and Drug Administration Safety Innovations Act (FDASIA) allows the agency to base such approvals on surrogate or intermediate clinical endpoints. Surrogate endpoints are biomarkers (laboratory measurements, radiographic images, or other measures) believed to predict clinical benefit without measuring it directly; intermediate clinical endpoints measure therapeutic effects considered to reasonably predict the clinical benefit of a drug.

The FDA decides whether to accept proposed endpoints based on “adequate and well controlled” scientific studies. Using surrogate or intermediate clinical endpoints can save time in the drug approval process. A sponsor must conduct phase 4 confirmatory trials to verify that those markers truly are predictive; if they are, the agency usually will terminate the requirement. Approval can be withdrawn or a labeled indication changed if phase 4 studies fail to show clinical benefit sufficient to justify risks associated with the drug.

Breakthrough therapy designation expedites development and review of drugs that treat serious conditions when preliminary evidence indicates substantial improvement over available therapies based on clinically significant endpoint(s). That is a matter of judgment depending on both the magnitude/duration of treatment effect and the importance of an observed clinical outcome. Preliminary clinical evidence should show a clear advantage over available therapies.

Clinically significant endpoints measure effects on irreversible morbidity or mortality (IMM) or on symptoms that represent serious consequences of a disease. They also can refer to findings that suggest an effect on IMM or serious symptoms (e.g., surrogate endpoints or pharmacodynamic biomarkers).

Breakthrough therapies are eligible for fast-track designation, intensive guidance on development program efficiencies (beginning as early as phase 1), and organizational commitment involving senior managers. If a sponsor has not requested breakthrough therapy designation, the FDA may suggest that it do so. Ideally, such a request should be received by the agency no later than the end of phase 2, and it will respond within 60 days.

The fast track process facilitates development and expedites review of drugs for treating serious conditions and filling unmet medical needs. This program addresses a broad range of serious conditions, generally based on whether a drug will affect patient survival and/or day-to-day functioning or will prevent a lesser condition becoming more serious. Companies developing fast-track drugs may have more frequent meetings and written communications with FDA than usual for discussing development plans, biomarkers, and so on. Fast-track drugs are eligible for accelerated approval and priority review as well as rolling review. In the latter, a sponsor submits completed sections of its biologic license application (BLA) or new drug application (NDA) for FDA review rather than waiting until every section is complete before submitting the entire application

Fast Track designation can be requested by a drug company at any time during product development. The agency reviews such requests and communicates a decision within 60 days. Early and frequent communication is encouraged throughout development and review of a fast-track drug to resolve questions and issues quickly, thus speeding drug approval and patient access.

Priority Review: Under the 1992 Prescription Drug User Fee Act (PDUFA), FDA agreed to improve its drug review times and create a two-tiered system of standard and priority reviews, the latter requiring action taken within six months (standard review takes 10 months). A priority-review designation directs overall attention and resources to evaluation of applications for drugs that present significant improvements in the safety/effectiveness of treatment, diagnosis, or prevention of serious conditions. The agency designates a review tier for every application; applicants may request priority review, which does not affect the clinical trial period.

SOURCE: HTTPS://WWW.FDA.GOV/FORPATIENTS/
APPROVALS/FAST/DEFAULT.HTM

At the BPI Conference, Andy Seipel (in regulatory CMC at Biogen) showed that regulatory affairs don’t end with product approval with his talk titled “Regulatory Lifecycle Management Strategies for Recently Commercialized Biologics.” Biopharmaceutical companies must strike a balance among speed to clinic, assurance of supplies, and controlling costs. Failure to do so, he warned, can cause delays and reimbursement reductions, decrease manufacturing flexibility and fractionate the supply chain, and ultimately waste resources. Despite the efforts of both the World Health Organization (WHO) and the International Council for Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH), global regulatory requirements remain unharmonized. Major markets such as the ICH signatories require full, independent review of each marketing application; emerging markets tend to leverage approvals from other reference markets when they review product candidates. And individual market requirements vary.

Thus, Seipel demonstrated, challenges arise because companies are unable to file marketing applications everywhere at same time. Application review timelines are long and variable. And once a product has been approved, process changes are not handled the same way everywhere. Their reviews can be slow and variable, as well, with refusals a possible outcome. Seipel advocated bundled submissions wherever possible, with their timing based on critical lifecycle management timelines. Companies should identify the difficult markets before initiating global submissions and adjust their application-submission timing (if feasible) to accommodate lifecycle management expectations. A strategic approach to regulatory dossiers — their level of detail increased or decreased based on market-specific requirements and risk assessment — can limit inclusion of inspectional or low-risk details that companies sometimes include just to reduce the potential for questions. Regional optimization efforts must take the benefits of global submission into consideration.

Work Smarter, Not Just Faster
It would be a mistake for any company to focus on speed to clinic/market to the exclusion of all other considerations. Product quality cannot be an afterthought. Phase-gating and six-sigma strategies help keep it a priority. At the BPI Conference, Regina Au (principal of new product planning at Biomarket Insight) highlighted the value of including marketing personnel on product-development teams in her talk, “Why Speed to IND Can Cause Major Issues and Risks Later in Development.” She said it’s never too early for business due diligence; it can be too late to fix problems later on in R&D. A product must satisfy many stakeholders to be successful. Missing just one of those can slow sales or even jeopardize market access. “Don’t try to do this yourself,” she cautioned. “Bring in the experts. A penny saved can waste dollars and time.”

The Global Bioproduction Summit held in San Diego last February also focused on issues of speeding products to market (4). There, MedImmune vice president Rakesh Dixit stated that more biologic drugs are being approved than at any other time in the past 10 years, which intensifies competition among those products treating the same diseases. “For example, more than 50 drugs are in development for some orphan diseases. The first one to market wins everything.” And new drugs cannot count on patent protection alone, with biosimilars and biobetters planned to cut into their sales as soon as possible. Douglas Williams (director of commercial development at Riffyn) says that that “data science is a lynchpin to this strategic shift” (4). Companies must make data-intensive decisions on compressed timescales. In other words: Work smarter to work faster.

But consultants Myoung Cha and Flora Yu of McKinsey and Company also point out that, although first-to-market advantage can be formidable, it’s not insurmountable (5). “Later entrants can maximize their chances by keeping pace with the leaders and establishing meaningful differentiation. . . [Although] first-mover advantage can be difficult to surmount when it comes to well-resourced and experienced players with long lead times, being first isn’t always as important as being best.” So clinical development and commercial strategy can be just as important as the timing of initial regulatory approval.

Technologies such as single-use systems and automation, high-throughput screening and analytics, and continuous processing are enabling biopharmaceutical companies to consider shortening their timelines (6–8). But success in doing so rides on taking a strategic approach, managing risk, making use of platforms and previous experience, and involving crossfunctional teams in decision making.